Antivirals are being used in the treatment of various forms of herpes simplex virus (HSV) infections. There are increasing reports of patients that do not benefit from these treatments because viruses isolated from these patients are resistant in vitro to the drug used. In life-threatening HSV infections, these patients would benefit from initial combined therapy until the isolate's sensitivity can be determined. In addition a combined modality of selective anti-HSV compounds may be of potential value in: 1) preventing the emergence of resistant viruses; 2) increasing the therapeutic effectiveness; 3) reducing toxicity; and 4) providing insight into their mode of action. In this proposal a number of promising antivirals will be tested in pairs in vitro and in vivo and the type of interaction determined. Using mice infected intracerebrally with HSV, our preliminary data showed that the combination of Acyclovir (ACV) and Vidarabine (ara-A) or its 5'-monophosphate (ara-AMP) was more effective in treating the resulting encephalitis than the agents singly. Efforts to optimize the efficacy of this combination will be undertaken. The sensitivity to combinations of ACV and ara-A in mice infected with ACV- and ara-A-resistant HSV strains will be determined. Levels of the two drugs in serum and CNS will be measured and compared to values obtained with single agents. The interaction of purified HSV-DNA polymerase with the triphosphates of ACV and ara-A will also be investigated. Various reports of clinical trials of new topical anti-HSV drugs have indicated that, whereas virus production is reduced, the duration of lesions and pain may not be greatly affected. We will, therefore, assess the effect of antivirals, steroid and nonsteroid anti-inflammatory agents, alone and in combination in cultures infected with HSV and in animal models, such as the mouse encephalitis and guinea pig skin model for HSV. The results of these studies will yield significant information on antiviral combinations which may be of clinical use for the life-threatening herpetic infections, such as encephalitis and neonatal herpes as well as the more frequent, less severe, orolabial and genital infections.